Isocoumarin-3-yl-acetic acid derivatives, for example, compounds represented by the formula: exhibit excellent immunoregulatory effects and inhibition effects on vascularization. Furthermore, they have the characteristic of low toxicity. Therefore, they are expected to be applied to the prevention and treatment of diseases associated with disorders of immunoregulatory effects and diseases associated with vascularization (see the gazette of WO97/48693). These isocoumarin derivatives have one asymmetric carbon in the structure, and there are two kinds of optically active substances for each. Various effects disclosed in the aforementioned gazette are caused by racemic substances. In general, there are cases in which various physiological activities of compounds differ between optically active substances or between an optically active substance and a racemic substance. Therefore, it is necessary to obtain optically active substances in order to acquire knowledge about physiological activities in more detail. In addition, according to the aforementioned gazette, they are prepared through several steps from 8-hydroxy-3-methyl-6-methoxy-isocoumarin. Although each step in this preparation method is excellent from the perspective that all of them proceed with a good yield, isocoumarin-3-yl-acetic acid derivatives with various substituents are not necessarily provided with good efficiency.
Therefore, the first object of the present invention is to provide a method of preparing optically active bodies of isocoumarin-3-yl-acetic acid derivatives including the compounds represented by the aforementioned formula (A) with good efficiency and intermediates for the preparation thereof.
The second object of the present invention is to provide a method of isocoumarin-3-yl-acetic acid derivatives, by which the derivatives can be prepared with good efficiency, and, by which, in particular, the substituent at the position 2 of an acetic acid chain, which can significantly affect the physiologically activity, can be varied.
The present inventors conducted extensive research to solve the first object mentioned above. They discovered that optically active isocoumarin-3-yl-acetic acid derivatives could be prepared with good efficiency by first deriving a ketene derivative from a racemic body of the isocoumarin-3-yl-acetic acid derivative, adding an optically active alcohol thereto, and then hydrolyzing an ester thus obtained. The first aspect of the present invention is based on such knowledge.
The present inventors conducted extensive research for solving the second object mentioned above. They discovered that isocoumarin-3-yl-acetic acid derivatives could be prepared with good efficiency by subjecting specific benzoic ester derivatives, which were not mentioned in the conventional technical literatures, to a cyclization reaction with a certain organic tin compound, and then subjecting the isocoumarin derivatives thus obtained to an addition reaction with carbon monoxide and oxygen in the presence of a transition metal catalyst. The second aspect of the present invention is based on such knowledge.